Camptothecin is a natural compound which has been isolated for the first time from the leaves and the bark of the Chinese plant called camptotheca acuminata (see Wall et al. J. Amer. Chem. Soc. 88:3888 (1966)). Camptothecin is a pentacyclic compound constituted by an indolizino[1,2-b]quinoline fragment fused with an (xcex1-hydroxylactone with six members. The carbon in position 20 which carries the xcex1-hydroxy group is asymmetrical and confers a rotatory power on the molecule. The natural form of camptothecin has an absolute xe2x80x9cSxe2x80x9d configuration as regards the carbon 20 and corresponds to the following formula: 
Camptothecin has an anti-proliferative activity in several cancerous cell lines, including the cell lines of human tumors of the colon, lung and breast (Suffness, M et al: The Alkaloids Chemistry and Pharmacology, Bross A., ed., Vol. 25, p. 73 (Acedemic Press, 1985)). It is suggested that the anti-proliferative activity of camptothecin is related to its inhibitory activity on DNA topoisomerase I.
It has been indicated that xcex1-hydroxylactone was an absolute requirement both for the in vivo and in vitro activity of campotothecin (Camptothecins: New Anticancer Agents, Putmesil, M et al, ed., p. 27 (CRC Press, 1995); Wall M. et al, Cancer Res. 55:753 (1995); Hertzberg et al, J. Med. Chem. 32:715 (1982) and Crow et al, J. Med. Chem. 35:4160 (1992)). The present invention relates to a new class of compounds of camptothecin, in which a xcex2-hydroxylactone replaces the natural xcex1-hydroxylactone of camptothecin. The compounds according to the present invention present a powerful biological activity which is unexpected with regard to the state of the prior art.
Therefore a subject of the invention is new analogues of camptothecin which differ from all known derivatives of camptothecin in the sense that they contain xcex2-hydroxylactone (or its open hydroxycarboxylic form) instead of an xcex1-hydroxylactone (or its open hydroxycarboxylic form); or a pharmaceutically acceptable salt of one of the latter. By derivative of camptothecin is meant a compound having the same structural skeleton as that of camptothecin (i.e. an indolizino[1,2-b]quinoline fragment fused with an xcex1-hydroxylactone with six members), with or without other chemical substitutions on the skeletal structure. Different derivatives of camptothecin are well known by specialists, as described hereafter. By xcex2-hydroxylactone is meant a lactone which contains an additional carbon atom between the carbon of the carboxyl and the xcex1-carbon carrying the hydroxyl group in the xcex1-hydroxylactone.
An analogue of camptothecin according to the invention can therefore contain substitutions on the indolizino[1,2-b]quinoline fragment (for example in order to improve the solubility of the compound), or on the open or closed xcex2-hydroxylactone (for example in order to improve the stability of the compound). Examples of substitutions on the closed xcex2-hydroxylactone include an alkyl substitution (for example ethyl) on the xcex2-carbon. Examples of substitutions on the open xcex2-hydroxylactone include alkyl substitutions on the xcex2-carbon, substitutions (for example an amidation) on the resultant carboxylic acid and substitutions (for example an esterification) or suppressions of the resultant hydroxyl group.
Preferred xcex2-hydroxylactone camptothecin analogues are notably those in which the pentacyclic skeletton is substituted at least once by an halogen atom in any of positions 9, 10, 11 or 12.
The invention first relates to compounds of general formula (B1) and (B2) 
in racemic or enantiomeric form or any combinations of these forms, in which
R1 represents a lower alkyl; a lower alkenyl, a lower alkynyl, a lower haloalkyl, a lower alkoxy lower alkyl or lower alkylthio lower alkyl;
R2, R3 and R4 represent, independently, H, halo, lower haloalkyl, lower alkyl, lower alkenyl, cyano, lower cyanoalkyl, nitro, lower nitroalkyl, amido, lower amidoalkyl, hydrazino, lower hydrazinoalkyl, azido, lower azidoalkyl, (CH2)mNR6R7, (CH2)mOR6, (CH2)mSR6, (CH2)mCO2R6, (CH2)mNR6C(O)R8, (CH2)mC(O)R8, (CH2)mOC(O)R8, O(CH2)mNR6R7, OC(O)NR6R7, OC(O)(CH2)mCO2R6 or (CH2)n[Nxe2x95x90X], OC(O)[Nxe2x95x90X], (CH2)mOC(O)[Nxe2x95x90X] (in which [Nxe2x95x90X], in this invention, represents a heterocyclic group with 4 to 7 members with the nitrogen atom N, which is a member of the heterocyclic group, and X represents the remaining members, which are necessary to complete the heterocylic group; selected from the group constituted by O, S, CH2, CH, N, NR9 and COR10), substituted or non substituted aryl or lower arylalkyl (i.e. substituted between once and four times on the aryl group or the heterocycle), in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl) or R2 and R3 form together a chain with 3 or 4 members in which the elements of the chain are selected from the group constituted by CH, CH2, O, S, N or NR9;
R5 represents H, halo, lower haloalkyl, lower alkyl, lower alkoxy, lower alkoxy lower alkyl, lower alkylthio lower alkyl, cycloalkyl, cycloalkyl lower alkyl, cyano, cyanoalkyl, lower alkyl lower sulphonylalkyl, lower hydroxyalkyl, nitro, (CH2)mC(O)R8, (CH2)mNR6C(O)R8, (CH2)mNR6R7, (CH2)mN(CH3)(CH2)nNR6R7, (CH2)mOC(O)R8, (CH2)mOC(O)NR6R7, (CH2)mS(O)qR11, (CH2)mP(O)R12R13, (CH2)2P(S)R12R13 or (CH2)n[Nxe2x95x90X], OC(O)[Nxe2x95x90X], (CH2)mOC(O)[Nxe2x95x90X], substituted or non substituted aryl or lower arylalkyl (i.e. substituted between once and four times on the aryl or heteroaryl group), in which the substituent is a lower alkyl, halo, hydroxy, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
R6 and R7 represent, independently, H, a lower alkyl, lower hydroxyalkyl, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy lower alkyl, lower haloalkyl, or substituted or non substituted aryl or lower arylalkyl (i.e. substituted between once and four times on the aryl group), in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
R8 represents H, a lower alkyl, lower hydroxyalkyl, amino, lower alkylamino, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy, lower alkoxy lower alkyl, lower haloalkyl, or substituted or non substituted aryl or lower arylalkyl (i.e. substituted between once and four times on the aryl group), in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
R9 represents H, a lower alkyl, lower haloalkyl, aryl, lower arylalkyl, or aryl or lower arylalkyl in which the aryl group is substituted by one or more groups chosen from the following radicals: lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
R10 represents H, a lower alkyl, lower haloalkyl, lower alkoxy, aryl or aryl substituted (i.e. having one to four substituents on the aryl group) by one or more groups chosen from the following radicals: lower alkyl, lower haloalkyl, lower hydroxyalkyl or lower alkoxy lower alkyl;
R11 represents a lower alkyl, aryl, (CH2)mOR14, (CH2)mSR14, (CH2)2NR14R15 or (CH2)m[Nxe2x95x90X];
R12 and R13 represent, independently, a lower alkyl, aryl, lower alkoxy, aryloxy or amino;
R14 and R15 represent, independently, H, lower alkyl or aryl;
R16 represents H or OR21;
R17 represents OR6 or NR6R7;
R18 and R19 represent, independently, H, halo, lower alkyl, lower alkoxy or hydroxy;
R20 represents H or halo;
R21 represents H, a lower alkyl, CHO or C(O)(CH2)mCH3;
Rp represents H or an easily cleavable group preferably chosen from the groups corresponding to the formula xe2x80x94C(O)xe2x80x94Axe2x80x94NR22R23, in which A represents a linear or branched alkylene radical optionally substituted by a radical chosen from the free, esterified or salified hydroxy, halogen, free, esterified or salified carboxy, amino, mono or dialkylamino radicals, while R22 and R23, independently, represent H, a lower alkyl, lower hydroxyalkyl, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy lower alkyl, lower haloalkyl, or substituted or non substituted aryl or lower arylalkyl (i.e., substituted one to four times on the aryl group), in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
m is an integer comprised between 0 and 6;
n is 1 or 2; and
q represents an integer from 0 to 2; and
[Nxe2x95x90X] represents a heterocyclic group with 4 to 7 members, X representing the chain necessary to complete said heterocyclic group and selected from the group constituted by O, S, CH2, CH, N, NR9 and COR10:
or pharmaceutically acceptable salts of the latter.
The invention especially relates to compounds of general formula (HCPT) 
in racemic or enantiomeric form or any combinations of these forms, in which
R1 represents a lower alkyl, a lower alkenyl, a lower alkynyl, a lower haloalkyl, a lower alkoxy lower alkyl or lower alkylthio lower alkyl;
R2, R3 and R4 represent, independently, H, halo, lower haloalkyl, lower alkyl, lower alkenyl, cyano, lower cyanoalkyl, nitro, lower nitroalkyl, amido, lower amidoalkyl, hydrazino, lower hydrazinoalkyl, azido, lower azidoalkyl, (CH2)mNR6R7, (CH2)mOR6, (CH2)mSR6, (CH2)mCO2R6, (CH2)mNR6C(O)R8, (CH2)mC(O)R8, (CH2)mOC(O)R8, O(CH2)mNR6R7, OC(O)NR6R7, OC(O)(CH2)mCO2R6 or (CH2)n[Nxe2x95x90X], OC(O)[Nxe2x95x90X], (CH2)mOC(O)[Nxe2x95x90X] (in which [Nxe2x95x90X], in this invention, represents a heterocyclic group with 4 to 7 members with the nitrogen atom N, which is a member of the heterocyclic group, and X represents the remaining members, which are necessary to complete the heterocylic group, selected from the group constituted by O, S, CH2, CH, N, NR9 and COR10), substituted or non substituted aryl or lower arylalkyl (i.e. substituted between once and four times on the aryl group or the heterocycle), in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl) or R2 and R3 form together a chain with 3 or 4 members in which the elements of the chain are selected from the group constituted by CH, CH2, O, S, N or NR9;
R5 represents H, halo, lower haloalkyl, lower alkyl, lower alkoxy, lower alkoxy lower alkyl, lower alkylthio lower alkyl, cycloalkyl, cycloalkyl lower alkyl, cyano, cyanoalkyl, lower alkyl lower sulphonylalkyl, lower hydroxyalkyl, nitro, (CH2)mC(O)R8, (CH2)mNR6C(O)R8, (CH2)mNR6R7, (CH2)mN(CH3)(CH2)nNR6R7, (CH2)mOC(O)R8, (CH2)mOC(O)NR6R7, (CH2)mS(O)qR11, (CH2)mP(O)R12R13, (CH2)2P(S)R12R13, substituted or non-substituted (CH2)n[Nxe2x95x90X] radical, OC(O)[Nxe2x95x90X], (CH2)mOC(O)[Nxe2x95x90X], substituted or non substituted aryl or lower arylalkyl (i.e. substituted between once and four times on the aryl or heteroaryl group), in which the substituent is a lower alkyl, halo, hydroxy, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
R6 and R7 represent, independently, H, a lower alkyl, lower hydroxyalkyl, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy lower alkyl, lower haloalkyl, or substituted or non substituted aryl or lower arylalkyl (i.e. substituted between once and four times on the aryl group), in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
R8 represents H, a lower alkyl, lower hydroxyalkyl, amino, lower alkylamino, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy, lower alkoxy lower alkyl, lower haloalkyl, or substituted or non substituted aryl or lower arylalkyl (i.e. substituted between once and four times on the aryl group), in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
R9 represents H, a lower alkyl, lower haloalkyl, aryl, lower arylalkyl, or aryl or lower arylalkyl in which the aryl group is substituted by one or more groups chosen from the following radicals: lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
R10 represents H, a lower alkyl, lower haloalkyl, lower alkoxy, aryl or aryl substituted (i.e. having one to four substituents on the aryl group) by one or more groups chosen from the following radicals: lower alkyl, lower haloalkyl, lower hydroxyalkyl or lower alkoxy lower alkyl;
R11 represents a lower alkyl, aryl, (CH2)mOR14, (CH2)mSR14, (CH2)2NR14R15 or (CH2)m[Nxe2x95x90X];
R12 and R13 represent, independently, a lower alkyl, aryl, lower alkoxy, aryloxy or amino;
R14 and R15 represent, independently, H, lower alkyl or aryl;
R16 represents H or OR21;
R17 represents OR6 or NR6R7;
R18 and R19 represent, independently, H, halo, lower alkyl, lower alkoxy or hydroxy;
R20 represents H or halo;
R21 represents H, a lower alkyl, CHO or C(O)(CH2)mCH3;
Rp represents H or an easily cleavable group preferably chosen from the groups corresponding to the formula xe2x80x94C(O)xe2x80x94Axe2x80x94NR22R23, in which A represents a linear or branched alkylene radical optionally substituted by a radical chosen from the free, esterified or salified hydroxy, halogen, free, esterified or salified carboxy, amino, mono or dialkylamino radicals, while R22 and R23, independently, represent H, a lower alkyl, lower hydroxyalkyl, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy lower alkyl, lower haloalkyl, or substituted or non substituted aryl or lower arylalkyl (i.e., substituted one to four times on the aryl group), in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
m is an integer comprised between 0 and 6;
n is 1 or 2; and
q represents an integer from 0 to 2; and
[Nxe2x95x90X] represents a heterocyclic group with 4 to 7 members, X representing the chain necessary to complete said heterocyclic group and selected from the group constituted by O, S, CH2, CH, N, NR9 and COR10;
or pharmaceutically acceptable salts of the latter.
For the compounds of general formulae (B1), (B2) and (HCPT) (and in extenso the compounds of general formulae (I) and (II)), the following preferences apply independently to the substituents:
R1 represents a lower alkyl, and preferably ethyl;
R2 represents halo;
R3 represents halo, lower alkyl or lower haloalkyl; when R3 is a lower alkyl, R3 is preferably methyl or ethyl;
R5 represents halo, lower alkyl, lower haloalkyl, lower aminoalkyl, substituted or non substituted (CH2)n[Nxe2x95x90X] radical, substituted or non substituted aryl or lower arylalkyl; preferred (CH2)n[Nxe2x95x90X] radicals include lower alkyl, and piperazines, especially methyl substituted piperazines;
R18 and R19 represent H.
R20 represents H.
The invention particularly relates to the following compounds which are described as examples of compounds responding to the general formula (B1) or the general formula (B2)
-tert-butyl 3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate;
-ethyl 3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate;
-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoic acid;
-methyl 3-hydroxy-3-[8-(methoxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate
-ethyl 2,2-difluoro-3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate;
-ethyl 3-hydroxy-3-(8-methyl-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl)pentanoate;
-tert-butyl 3-{8-[(acetyloxy)methyl]-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl}-3-hydroxypentanoate;
-5,12-diethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-3-[12-ethyl-8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]-3-hydroxypentanoic acid;
-8-ethyl-8-hydroxy-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-10,13-dione;
-10-(benzyloxy)-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-3-[2-(benzyloxy)-8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]-3-hydroxypentanoic acid (E);
-5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino [3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-11-[(dimethylamino)methyl]-5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-7-ethyl-7-hydroxy-7,8,11,14-tetrahydro-9H,12H-[1,3]dioxolo[4,5-g]oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-9,12-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9,11-dichloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino [3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-10-chloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5,10-dihydroxy-11-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5,12-diethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5-hydroxy-12-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dion;
-5-ethyl-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-10-fluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-10-fluoro-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino [3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino [3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino [3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-8-ethyl-8-hydroxy-16-[(4-methyl-1-piperazinyl)methyl]-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-10,13-dione;
-9-chloro-5-ethyl-10-fluoro-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[3,6-dihydro-1(2H)-pyridinylmethyl]-5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino [3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9,10-difluoro-5-hydroxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9,10-difluoro-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[(dimethylamino)methyl]-5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-{[benzyl(methyl)amino]methyl}-9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[(4-benzyl-1-piperazinyl)methyl]-9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[(4-benzyl-1-piperazinyl)methyl]-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[(4-benzyl-1-piperazinyl)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[(dimethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[(diethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione; -12-[3,6-dihydro-1 (2H)-pyridinylmethyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[(diisobutylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-12-[(dimethylamino)methyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[3,6-dihydro-1(2H)-pyridinylmethyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5-hydroxy-10-methoxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[(4-benzyl-1-piperazinyl)methyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-10-(benzyloxy)-5-ethyl-9-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3xe2x80x2,4xe2x80x2:6,7)indolizino[1,2-b]quinolin-5-yl 2-aminoacetate;
-5-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinolin-5-yl 3-aminopropanoate;
-2,9-diethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-11,14-dione;
-9-ethyl-9-hydroxy-2-methyl-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-11,14-dione;
-2-benzyl-9-ethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-11,14-dione;
-2-benzyl-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-11,14-dione;
-(+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-(+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]-4-methyl-hexahydropyridine;
or a pharmaceutically acceptable salt of the latter.
The invention more particularly relates to the following compounds corresponding to the formula (HCPT):
-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]-quinoline-3,15-dione;
-5,12-diethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-8-ethyl-8-hydroxy-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-10,13-dione;
-10-(benzyloxy)-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino [3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-11-[(dimethylamino)methyl]-5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-7-ethyl-7-hydroxy-7,8,11,14-tetrahydro-9H,12H-[1,3]dioxolo[4,5-g]-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-9,12-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-9,11-dichloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-10-chloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5,10-dihydroxy-11-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5,12-diethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5-hydroxy-12-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-10-fluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-10-fluoro-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-8-ethyl-8-hydroxy-16-[(4-methyl-1-piperazinyl)methyl]-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-10,13-dione;
-9-chloro-5-ethyl-10-fluoro-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[3,6-dihydro-1(2H)-pyridinylmethyl]-5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9,10-difluoro-5-hydroxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9,10-difluoro-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[(dimethylamino)methyl]-5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-{[benzyl(methyl)amino]methyl}-9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[(4-benzyl-1-piperazinyl)methyl]9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[(4-benzyl-1-piperazinyl)methyl]5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[(4-benzyl-1-piperazinyl)methyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[(dimethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[(diethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[3,6-dihydro-1(2H)-pyridinylmethyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[(diisobutylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-12-[(dimethylamino)methyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino [1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[3,6-dihydro-1(2H)-pyridinylmethyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5-hydroxy-10-methoxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[(4-benzyl-1-piperazinyl)methyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-10-(benzyloxy)-5-ethyl-9-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinolin-5-yl 2-aminoacetate;
-5-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinolin-5-yl 3-aminopropanoate;
-2,9-diethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-11,14-dione;
-9-ethyl-9-hydroxy-2-methyl-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-11,14-dione;
-2-benzyl-9-ethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-11,14-dione;
-2-benzyl-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]-oxazino[5,6-f]oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-11,14-dione;
-(+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-(+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]4-methyl-hexahydropyridine;
or pharmaceutically acceptable salts of the latter.
Among the above list of compounds, the following are preferred:
-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]-quinoline-3,15-dione;
-5,12-diethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-8-ethyl-8-hydroxy-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-10,13-dione;
-5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-7-ethyl-7-hydroxy-7,8,11,14-tetrahydro-9H,12H-[1,3]dioxolo[4,5-g]-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-9,12-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-9,11-dichloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-10-chloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5,12-diethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5-hydroxy-12-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[3,6-dihydro-1(2H)-pyridinylmethyl]5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9,10-difluoro-5-hydroxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9,10-difluoro-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[(dimethylamino)methyl]5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[(4-benzyl-1-piperazinyl)methyl]9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[(diethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[3,6-dihydro-1(2H)-pyridinylmethyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[(diisobutylamino)methyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino [1,2-b]quinoline-3,15-dione;
-9-chloro-12-[(dimethylamino)methyl]5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-2,9-diethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-11,14-dione;
-9-ethyl-9-hydroxy-2-methyl-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-11,14-dione;
-2-benzyl-9-ethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-11,14-dione;
-2-benzyl-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]-oxazino[5,6-f]oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-11,14-dione;
-(+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-(+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]4-methyl-hexahydropyridine;
or a pharmaceutically acceptable salt of the latter.
Among the above list of compounds, the following are more preferred:
-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino [1,2-b]-quinoline-3,15-dione;
-5,12-diethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-8-ethyl-8-hydroxy-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-10,13-dione;
-5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-7-ethyl-7-hydroxy-7,8,11,14-tetrahydro-9H,12H-[1,3]dioxolo[4,5-g]-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-9,12-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2,:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-10-chloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5,12-diethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
5-5-ethyl-5-hydroxy-12-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9,10-difluoro-5-hydroxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[(diethylamino)methyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-12-[3,6-dihydro-1(2H)-pyridinylmethyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-2,9-diethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-11,14-dione;
-9-ethyl-9-hydroxy-2-methyl-1,2,3,9,10,16-hexahydro-1,3H-[1,3]oxazino[5,6-f]-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-11,14-dione;
-2-benzyl-9-ethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-11,14-dione;
-2-benzyl-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]-oxazino[5,6-f]oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-11,14-dione;
-(+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-(+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]4-methyl-hexahydropyridine;
or a pharmaceutically acceptable salt of the latter.
Among the above lists of compounds, particularly preferred compounds for the present invention are the following:
-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]-quinoline-3,15-dione;
-5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2,:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-5-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino [3xe2x80x2,4xe2x80x2:6,7]-indolizino[1,2-b]quinoline-3,15-dione;
-(+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-(+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]4-methyl-hexahydropyridine;
or a pharmaceutically acceptable salt of the latter.
Among the above lists of compounds, more particularly preferred compounds for the present invention are the following:
-(+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15-dione;
-(+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]-4-methyl-hexahydropyridine;
or a pharmaceutically acceptable salt of the latter.
A more particular subject of the invention is the compounds of general formula (I) and general formula (II), 
in racemic or enantiomeric form or any combinations of these forms, in which
R1 represents a lower alkyl, a lower alkenyl, a lower alkynyl, a lower haloalkyl, a lower alkoxy lower alkyl or lower alkylthio lower alkyl;
R2, R3 and R4 represent, independently, H, halo, lower haloalkyl, lower alkyl, lower alkenyl, cyano, lower cyanoalkyl, nitro, lower nitroalkyl, amido, lower amidoalkyl, hydrazino, lower hydrazinoalkyl, azido, lower azidoalkyl, (CH2)mNR6R7, (CH2)mOR6, (CH2)mSR6, (CH2)mCO2R6, (CH2)mNR6C(O)R8, (CH2)mC(O)R8, (CH2)mOC(O)R8, O(CH2)mNR6R7, OC(O)NR6R7, OC(O)(CH2)mCO2R6 or (CH2)n[Nxe2x95x90X], OC(O)[Nxe2x95x90X], (CH2)mOC(O)[Nxe2x95x90X] (in which [Nxe2x95x90X], in this invention, represents a heterocyclic group with 4 to 7 members with the nitrogen atom N, which is a member of the heterocyclic group, and X represents the remaining members, which are necessary to complete the heterocylic group, selected from the group constituted by O, S, CH2, CH, N, NR9 and COR10), substituted or non substituted aryl or lower arylalkyl (i.e. substituted between once and four times on the aryl group or the heterocycle), in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl) or R2 and R3 form together a chain with 3 or 4 members in which the elements of the chain are selected from the group constituted by CH, CH2, O, S, N or NR9;
R5 represents H, halo, lower haloalkyl, lower alkyl, lower alkoxy, lower alkoxy lower alkyl, lower alkylthio lower alkyl, cycloalkyl, cycloalkyl lower alkyl, cyano, cyanoalkyl, lower alkyl lower sulphonylalkyl, lower hydroxyalkyl, nitro, (CH2)mC(O)R8, (CH2)mNR6C(O)R8, (CH2)mNR6R7, (CH2)mN(CH3)(CH2)nNR6R7, (CH2)mOC(O)R8, (CH2)mOC(O)NR6R7, (CH2)mS(O)qR11, (CH2)mP(O)R12R13, (CH2)2P(S)R12R13 or (CH2)n[Nxe2x95x90X], OC(O)[Nxe2x95x90X], (CH2)mOC(O)[Nxe2x95x90X], substituted or non substituted aryl or lower arylalkyl (i.e. substituted between once and four times on the aryl or heteroaryl group), in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
R6 and R7 represent, independently, H, a lower alkyl, lower hydroxyalkyl, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy lower alkyl, lower haloalkyl, or substituted or non substituted aryl or lower arylalkyl (i.e. substituted between once and four times on the aryl group), in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
R8 represents H, a lower alkyl, lower hydroxyalkyl, amino, lower alkylamino, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy, lower alkoxy lower alkyl, lower haloalkyl, or substituted or non substituted aryl or lower arylalkyl (i.e. substituted between once and four times on the aryl group), in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
R9 represents H, a lower alkyl, lower haloalkyl, aryl, lower arylalkyl, or aryl or lower arylalkyl in which the aryl group is substituted by one or more groups chosen from the following radicals: lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
R10 represents H, a lower alkyl, lower haloalkyl, lower alkoxy, aryl or aryl substituted (i.e. having one to four substituents on the aryl group) by one or more groups chosen from the following radicals: lower alkyl, lower haloalkyl, lower hydroxyalkyl or lower alkoxy lower alkyl;
R11 represents a lower alkyl, aryl, (CH2)mOR14, (CH2)mSR14, (CH2)2NR14R15 or (CH2)m[Nxe2x95x90X];
R12 and R13 represent, independently, a lower alkyl, aryl, lower alkoxy, aryloxy or amino;
R14 and R15 represent, independently, H, lower alkyl or aryl;
R16 represents H or OR21;
R17 represents OR6 or NR6R7;
R18 and R19 represent, independently, H, halo, lower alkyl, lower alkoxy or hydroxy;
R20 represents H or halo;
R21 represents H, a lower alkyl, CHO or C(O)(CH2)mCH3;
m is an integer comprised between 0 and 6;
n is 1 or 2; and
q represents an integer from 0 to 2; and
[Nxe2x95x90X] represents a heterocyclic group with 4 to 7 members, X representing the chain necessary to complete said heterocyclic group and selected from the group constituted by O, S, CH2, CH, N, NR9 and COR10:
or a pharmaceutically acceptable salt of the latter.
A particular subject of the invention is the compounds of formulae I and II as defined above in which R1 represents a lower alkyl, lower alkenyl, lower haloalkyl, lower alkoxy lower alkyl or lower alkylthio lower alkyl; R5 represents H, halo, lower haloalkyl, lower alkyl, lower alkoxy, lower alkoxy lower alkyl, lower alkylthio lower alkyl, cycloalkyl, cycloalkyl lower alkyl, cyano, cyanoalkyl, lower hydroxyalkyl, nitro, (CH2)mC(O)R8, (CH2)mNR6C(O)R8, (CH2)mNR6R7, (CH2)mN(CH3)(CH2)nNR6R7, (CH2)mOC(O)R8, (CH2)mOC(O)NR6R7, or (CH2)n[Nxe2x95x90X], OC(O)[Nxe2x95x90X], (CH2)mOC(O)[Nxe2x95x90X], substituted or non substituted aryl or lower arylalkyl; R12 and R13 represent, independently, a lower alkyl; R16 represents OR21; and R18, R19 and R20 represent H.
The invention has more particularly as its subject matter the compounds of formula (I) and (II) as is defined above in which R1 represents a lower alkyl, lower alkenyl, lower haloalkyl or lower alkoxy lower alkyl; R2, R3 and R4 represent, independently, H, halo, lower haloalkyl, lower alkyl, nitro, amido, lower amidoalkyl, hydrazino, lower hydrazinoalkyl, azido, lower azidoalkyl, (CH2)mNR6R7, (CH2)mOR6, (CH2)mSR6, (CH2)mC(O)R8, (CH2)n[Nxe2x95x90X], or (CH2)mOC(O)[Nxe2x95x90X] substituted or non substituted, or OC(O)[Nxe2x95x90X]; or R2 and R3 form together a chain with 3 or 4 members in which the elements of the chain are selected from the group constituted by CH, CH2, O, S, N or NR9; R5 represents H, halo, lower haloalkyl, lower alkyl, lower alkoxy, lower alkoxy lower alkyl, lower alkylthio lower alkyl, lower hydroxyalkyl, nitro, (CH2)mC(O)R8, (CH2)mNR6C(O)R8, (CH2)mNR6R7, (CH2)mN(CH3)(CH2)nNR6R7(CH2)mOC(O)R8, (CH2)mOC(O)NR6R7, or (CH2)n[Nxe2x95x90X], OC(O)[Nxe2x95x90X] substituted or non substituted or (CH2)mOC(O)[Nxe2x95x90X]; R6 and R7 represent, independently, H, a lower alkyl, lower hydroxyalkyl, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkoxy lower alkyl, lower haloalkyl, or substituted or non substituted aryl or lower arylalkyl; R8 represents H, a lower alkyl, lower hydroxyalkyl, lower alkylamino, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy, lower alkoxy lower alkyl, lower haloalkyl, or substituted or non substituted aryl or lower arylalkyl; R9 represents H, a lower alkyl or lower haloalkyl; R10 represents H, a lower alkyl, lower haloalkyl or lower alkoxy; R9 represents H or lower alkyl; and R14 and R15 represent, independently, H or lower alkyl.
In a more preferred manner, R2 represents H or halo and preferably H, chloro or fluoro; and R3 represents H, a lower alkyl, halo or OR6 in which R6 represents H, a lower alkyl or a lower arylalkyl and preferably H, fluoro, chloro, methyl or methoxy. Also in a more preferred manner, R2 and R3 together form a methylenedioxy or an ethylenedioxy.
A more particular subject of the invention is the compounds of formula (I) and (II) for which R2 represents a hydrogen or halogen atom, R3 represents a halogen atom, a lower alkyl or a lower alkoxy, R4 and R16 represent hydrogen atoms, and R18, R19 and R20 represent hydrogen atoms; or a pharmaceutically acceptable salt of the latter. An aminoalkyl radical will then preferably be chosen for R5.
A more particular subject of the invention is the products described hereafter in the examples and corresponding to the following formulae:
-5-ethyl-9,10-difluoro4,5-dihydro-5-hydroxy-12-(1,2,5,6-tetrahydopyridinomethyl-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione hydrochloride
-5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(4-methyl piperidinomethyl)-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-pyrrolidinomethyl-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(4-methyl piperazinomethyl-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-piperidinomethyl-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-dimethylamino-methyl-1 H-oxepino(3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-morpholino methyl-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methylpiperazinomethyl)-1H-oxepino(3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,3H)-dione
-12-benzylpiperazinomethyl-9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-12-(4-benzylpiperazinomethyl)-9-chloro-5-ethyl4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-piperidinomethyl-1H-oxepino(3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-12-(4-benzylpiperazinomethyl)-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-12-(4-benzylpiperazinomethyl)-5-ethyl-9-fluoro4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-5-ethyl-9-fluoro4,5-dihydro-5-hydroxy-10-methyl-12-dimethylaminomethyl-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-5-ethyl-12-diethylaminomethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methyl piperidinomethyl)-1H-oxepino[3xe2x80x2,4:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-pyrrolidinomethyl-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-(1,2,5,6-tetrahydropyridinomethyl)-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-12-diisobutylaminomethyl-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methylpiperazinomethyl)-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-12-piperidino methyl-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-dimethylamninomethyl-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-piperidinomethyl-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione hydrochloride
-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(1,2,5,6-tetrahydropyridinomethyl)-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H13H)-dione hydrochloride
-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methyl piperidinomethyl)-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methyl piperazinomethyl)-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-pyrrolidinomethyl-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-12-(4-benzylpiperazinomethyl)-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7)indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-(-4-methylpiperidino methyl)-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;
-10-benzyloxy-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;
-5-ethyl-9-fluoro-4,5-dihydro-5,10-dihydroxy-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;
or a pharmaceutically acceptable salt of the latter.
A more particular subject of the invention is the compounds of formula (I) as defined above, in which R1 represents the ethyl group; R2 and R3 represent, independently, H, a lower alkyl, halo, lower alkyl halo or (CH2)mOR6, or R2 and R3 form together a methylenedioxy or an ethylenedioxy; R4 and R5 represent, independently, H, a lower alkyl, (CH2)mNR6R7, or (CH2)n[Nxe2x95x90X] non substituted or substituted by, a lower alkyl; R20 represents H and R17 represents OR6, in which R6 represents H or a lower alkyl, or NR6R7 in which R6 and R7, independently, represent H, a lower alkyl, aryl or lower alkyl aryl. Preferably, R4 represents H or (CH2)mNR6R7, in which R6 and R7 represent, independently H or a lower alkyl; R5 represents H, a lower alkyl or (CH2)n[Nxe2x95x90X] non substituted or substituted by a lower alkyl; and R17 represents OR6 in which R6 represents H or a lower alkyl; or a pharmaceutically acceptable salt of the latter. As an example of substituted or non substituted [Nxe2x95x90X], there can be mentioned the piperidyl, morpholinyl, piperazinyl, imidazolyl and 4-methylpiperazinyl radical.
In a more preferred manner, R2 represents H or halo and preferably H, chloro or fluoro; R3 represents H, a lower alkyl, halo or OR6 in which R6 represents H, a lower alkyl or a lower alkyl aryl and preferably H, fluoro, chloro, methyl or methoxy. Also in a more preferred manner R2 and R3 form together dioxymethylene or dioxyethylene.
A more particular subject of the invention is the products described hereafter in the examples, in particular the products corresponding to the following formulae:
-5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(4-methyl piperidinomethyl)-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;
-5-ethyl-12-diethylaminomethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;
-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methyl piperidinomethyl)-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;
-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-pyrrolidinomethyl-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;
-9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-piperidinomethyl-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione hydrochloride
-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methyl piperidinomethyl)-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;
-9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methylpiperidino methyl)-1H-oxepino[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;
or a pharmaceutically acceptable salt of the latter.
Camptothecin and certain of its analogues are not hydrosoluble, which makes their administration by parenteral route difficult. Hydrosoluble derivatives of camptothecin have been prepared where rings A and B carry salifiable substituents (cf. for example U.S. Pat. Nos. 4,981,968, 5,049,668, EP 540,099). However, these products revealed an antitumoral activity which was reduced with respect to that of non-hydrosoluble derivatives. Other hydrosoluble derivatives of camptothecin have also been prepared where the hydroxyl group in position 20 is esterified by an acid carrying a salifiable radical such as for example glycine (cf. U.S. Pat. No. 4,943,579 and PCT No. WO 96/02546). These derivatives are designated by a person skilled in the art under the name xe2x80x9cprodrug formsxe2x80x9d as they are not biologically active in themselves, but only after a first metabolization phase once administered to the patient. The prodrug forms of the xcex1-hydroxylactone analogues of camptothecin have shown a good anti-tumoral effectiveness in animals and clinically, but accompanied by damaging side-effects such as the appearance of serious diarrhoeas which can put the patient""s life in danger. It is therefore necessary to develop hydrosoluble analogues of camptothecin which are more effective and better tolerated.
Hydrosolubility of the camptothecin analogues being important, some compounds according to the present invention have also been designed in order to possess this property as well.
Two solutions were chosen in order to increase the hydrosolubility of the camptothecin analogues: the first consists in grafting an oxazine onto the A ring of the molecule, and the second in designing prodrug forms by acetylating the hydroxy function of the xcex2-hydroxylactone.
More specifically, among this new class of camptothecin analogues, the compounds according to the present invention are either analogues modified by fixation of an oxazine ring on carbons 10 and 11 or prodrug forms in which a xcex2-hydroxylactone replaces the natural xcex1-hydroxylactone of camptothecin. The compounds of the present invention are therefore camptothecin analogue xcex2-hydroxylactones on which an oxazine ring or hydrosoluble prodrugs have been grafted and present a powerful biological activity which is unexpected in the light of the state of the prior art.
Another object of the invention is therefore the compounds of formula (I)OP and formula (II)OP: 
in racemic or enantiomeric form or any combinations of these forms, in which
R1 represents a lower alkyl, a lower alkenyl, a lower alkynyl, a lower haloalkyl, a lower alkoxy lower alkyl or lower alkylthio lower alkyl;
R2, R3 and R4 represent, independently, H, halo, lower haloalkyl, lower alkyl, lower alkenyl, cyano, lower cyanoalkyl, nitro, lower nitroalkyl, amido, lower amidoalkyl, hydrazino, lower hydrazinoalkyl, azido, lower azidoalkyl, (CH2)mNR6R7, (CH2)mOR6, (CH2)mSR6, (CH2)mCO2R6, (CH2)mNR6C(O)R8, (CH2)mC(O)R8, (CH2)mOC(O)R8, O(CH2)mNR6R7, OC(O)NR6R7, OC(O)(CH2)mCO2R6 or (CH2)n[Nxe2x95x90X], OC(O)[Nxe2x95x90X], (CH2)mOC(O)[Nxe2x95x90X] (in which [Nxe2x95x90X], in this invention, represents a heterocyclic group with 4 to 7 members with the nitrogen atom N, which is a member of the heterocyclic group, and X represents the remaining members, which are necessary to complete the heterocylic group, selected from the group constituted by O, S, CH2, CH, N, NR9 and COR10), aryl or lower arylalkyl substituted (i.e. substituted between once and four times on the aryl group or the heterocycle) or non substituted, in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl or R2 and R3 or R3 and R4 form together a chain with 3 or 4 members in which the elements of the chain are selected from the group constituted by CH, CH2, O, S, N or NR9;
R5 represents H, halo, lower haloalkyl, lower alkyl, lower alkoxy, lower alkoxy lower alkyl, lower alkylthio lower alkyl, cycloalkyl, cycloalkyl lower alkyl, cyano, cyanoalkyl, lower alkyl lower sulphonylalkyl, lower hydroxyalkyl, nitro, (CH2)mC(O)R8, (CH2)mNR6C(O)R8, (CH2)mNR6R7, (CH2)mN(CH3)(CH2)nNR6R7, (CH2)mOC(O)R8, (CH2)mOC(O)NR6R7, (CH2)mS(O)qR11, (CH2)mP(O)R12R13(CH2)2P(S)R12R13 or (CH2)n[Nxe2x95x90X], OC(O)[Nxe2x95x90X], (CH2)mOC(O)[Nxe2x95x90X], substituted or non substituted aryl or lower alkyl aryl (i.e. substituted between once and four times on the aryl or heteroaryl group), in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
R6 and R7 represent, independently, H, a lower alkyl, lower hydroxyalkyl, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy lower alkyl, lower haloalkyl, or a substituted or non substituted aryl or lower arylalkyl (i.e. substituted between once and four times on the aryl group), in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
R8 represents H, a lower alkyl, lower hydroxyalkyl, amino, lower alkylamino, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy, lower alkoxy lower alkyl, lower haloalkyl, or substituted or non substituted aryl or lower arylalkyl (i.e. substituted between once and four times on the aryl group), in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;,
R9 represents H, a lower alkyl, lower haloalkyl, aryl, lower arylalkyl, or aryl or lower arylalkyl in which the aryl group is substituted by one or more groups chosen from the following radicals: lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
R10 represents H, a lower alkyl, lower haloalkyl, lower alkoxy, aryl or aryl substituted (i.e. having one to four substituents on the aryl group) by one or more groups chosen from the following radicals: lower alkyl, lower haloalkyl, lower hydroxyalkyl or lower alkoxy lower allyl;
R11 represents a lower alkyl, aryl, (CH2)mOR14, (CH2)mSR14, (CH2)2NR14R15 or (CH2)m[Nxe2x95x90X];
R12 and R13 represent, independently, a lower alkyl, aryl, lower alkoxy, aryloxy or amino;
R14 and R15 represent, independently, H, lower alkyl or aryl;
R16 represents H or OR21;
R17 represents OR6 or NR6R7;
R18 and R19 represent, independently, H, halo, lower alkyl, lower alkoxy or hydroxy;
R20 represents H or halo;
R21 represents H, a lower alkyl, CHO or C(O)CH2)mCH3;
Rp represents H or an easily cleavable group preferably chosen from the groups corresponding to the formula xe2x80x94C(O)xe2x80x94Axe2x80x94NR22R23, in which A represents a linear or branched alkylene radical optionally substituted by a radical chosen from the free, esterified or salified hydroxy, halogen, free, esterified or salified carboxy, amino, mono or dialkylamino radicals, while R22 and R23, independently, represent H, a lower alkyl, lower hydroxyalkyl, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy lower alkyl, lower haloalkyl, or substituted or non substituted aryl or lower arylalkyl (i.e., substituted one to four times on the aryl group), in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
m is an integer comprised between 0 and 6;
n is 1 or 2; and
q represents an integer from 0 to 2; and
[Nxe2x95x90X] represents a heterocyclic group with 4 to 7 members, X representing the chain necessary to complete said heterocyclic group and selected from the group constituted by O, S, CH2, CH, N, NR9 and COR10;
it being understood that when Rp is a hydrogen atom, R3 and R4 together form a chain with 3 or 4 members; or a pharmaceutically acceptable salt of the latter.
As concerns the oxazin-grafted forms of the invention, R2 preferably represents a radical chosen from the group consisting of H, halo or lower alkyl.
As concerns the prodrug forms of the invention (those for which Rp is not a hydrogen atom), the products of general formula (I)OP are preferred. Preferably, R2 and R3 then represent, independently, a radical chosen from the group consisting of halo or lower alkyl.
Examples of substituted camptothecins used as starting products can be found in the U.S. Pat. Nos. 4,473,692, 4,604,463, 4,894,956, 5,162,532, 5,395,939, 5,315,007, 5,264,579, 5,258,516, 5,254,690, 5,212,317 and 5,341,745, the PCT Patent Applications Nos. US91/08028, US94/06451, US90/05172, US92/04611, US93/10987, US91/09598, EP94/03058 and EP95/00393 and the European Patent Application Nos. 325 247, 495 432, 321 122 and 540 099.
For the compounds comprising an oxazine ring:
a xcex2-hydroxylactonic compound of general formula D 
in which R3 is a hydroxyl radical, R4 is H and R1, R2, R5, R18, R19 and R20 have the meaning indicated above is treated with a primary amine, under Mannich""s conditions, in order to obtain a xcex2-hydroxylactonic compound of general formula Ia 
in which R1, R2, R5, R9, R18, R19 and R20 have the meaning indicated above.
This process consists in heating the starting product in the presence of a primary amine such as benzylamine, of formaldehyde in an acid solvent such as acetic acid or propionic acid at a temperature of 30xc2x0 C. to 80xc2x0 C. for a period of 0.5 to 5 hours. Alternatively, a suspension of starting product in acetic acid with a tri-N-substituted hexahydrotriazine such as hexahydro-1,3,5-trimethyl triazine, 1,3,5-triethylhexahydro triazine or 1,3,5-tribenzyl hexahydrotriazine can be heated at a temperature of 30xc2x0 C. to 80xc2x0 C. for a period of 0.5 to 5 hours.
the lactone of general formula Ia is opened optionally in a basic medium in order to produce after neutralization the compound of formula IIa 
in which R1, R2, R5, R9, R17, R18, R19 and R20 have the meaning indicated above; R16 represents OR21 in which R21 represents H or a lower alkyl; and R17 represents OR6 or NHR6 and R6 represents H, a lower alkyl, cycloalkyl, lower cycloalkyl alkyl, lower alkenyl, lower alkoxy lower alkyl, or aryl or lower aryl alkyl.
the said compound of general formula D or Ia is optionally acylated, preferably with a derivative of the C(O)xe2x80x94Axe2x80x94Nxe2x80x94R22R23 radical as defined above in order to produce the xcex2-hydroxylactonic compound of general formula Ib, i.e. (I)OP with Rp different from H (prodrug form of the invention).
in the same manner as with the lactone Ia, the lactone Ib can be opened in order to produce hydroxyacid IIb.
The opening of the lactone ring in a basic medium can more generally be used in order to convert products of general formula (B1) in products of general formula (B2).
In the above process, the R2, R3, R4 and R5 groups can be protected if necessary according to standard protection methods (Greene, T., Protective Groups in Organic Synthesis 10-86 (John Wiley and Sons 1981)). If at least one of the R22 or R23 groups is H, or contains at least one function which is chemically incompatible with the acylation process such as, for example, a primary or secondary amine, it is then necessary to use a protective group which is resistent to acylation conditions. A protective group commonly used for the amines is tert-butyloxycarbonyl (BOC). The acylation reaction is then carried out as described above, then the protective group is cleaved, for example by treatment with trifluoroacetic acid in the case of BOC, in order to produce the compound of general formula (I) or (II). Use of protective groups is known to a person skilled in the art (for other examples, reference can be made to Greene, T., Protective Groups in Organic Synthesis, John Wiley and Sons, 1981).
The preparation of the compounds of general formula D is described later in the present application.
As it is used here, the term lower with reference to the alkyl, alkylthio and alkoxy groups designates linear or branched saturated aliphatic hydrocarbon groups containing 1 to 6 carbons, such as for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methylthio, ethylthio, methoxy and ethoxy. With reference to the alkenyl or alkynyl groups, the term lower designates groups containing 2 to 6 carbon atoms and one or more double or triple bonds, such as for example, the vinyl, allyl, isopropenyl, pentenyl, hexanyl, ethynyl propenyl, propynyl and butynyl groups. The term cycloalkyl designates a ring with 3 to 7 carbons, such as for example, the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups. The term aryl designates a mono- di- or tricyclic hydrocarbon compound with at least one aromatic ring, each ring containing a maximum of 7 members, such as for example, phenyl, naphthyl, anthracyl, biphenyl or indenyl. The term halo signifies chloro, bromo, iodo or fluoro. The radicals corresponding to the expressions lower haloalkyl, lower cyanoalkyl, lower nitroalkyl, lower amidoalkyl, lower hydrazinoalkyl, lower azidoalkyl, lower arylalkyl, lower hydroxyalkyl, lower alkoxy lower alkyl, lower alkylthio lower alkyl, and lower alkyl lower sulphonylalkyl are substituted, respectively, by one to three halo, cyano, nitro, amido, hydrazino, azido, aryl, hydroxy, lower alkoxy, lower alkylthio or lower sulphonylalkyl groups. The lower alkylamino radical can contain one or two lower alkyl groups and represent, for example, NHCH3, NH(CH2CH3, N(CH3)2 or N(CH3)(CH2CH3). Examples of [Nxe2x95x90X] include the piperidinyl, morpholinyl, piperizinyl and imidazolyl groups.
As has been observed for camptothecin, the carbon atom carrying the hydroxy function in the xcex2-hydroxylactone or the xcex2-hydroxycarboxylate group of the compounds according to the present invention, is asymmetrical. Consequently, the compounds according to the present invention have two possible enantiomeric forms, i.e. under xe2x80x9cRxe2x80x9d and xe2x80x9cSxe2x80x9d configurations. The present invention includes the two enantiomeric forms and any combinations of these forms, including xe2x80x9cRSxe2x80x9d racemic mixtures. In an effort to simplify matters, when no specific configuration is indicated in the structural formulae, it should be understood that the two enantiomeric forms and their mixtures are represented.
A subject of the invention is also preparation processes for the compounds of general formulae (B1) and (B2), either starting with camptothecin or substituted camptothecins, or by total chemical synthesis.
Therefore the invention relates to a preparation process for the compounds of formulae (B1) and (B2) according to the invention, and in particular the products the formulae of which are indicated above, starting with camptothecin or substituted camptothecins characterized in that:
camptothecin xcex1-hydroxylactone of general formula 
in which R1, R2, R3, R4, R5 and R20 have the meaning indicated above, is reduced in order to obtain the xcex1-hydroxylactol of general formula A 
in which R1, R2, R3, R4, R5 and R20 have the meaning indicated above,
in compound A thus formed, the carbonxe2x80x94carbon bond linking the adjacent carbinols, is cut by treatment with an appropriate oxidizing agent so as to produce a compound of formula B 
in which R1, R2, R3, R4, R5 and R20 have the meaning indicated above,
then treatment is carried out with a functionalized alkylating agent and the formyl function of the compound of formula B is cut in order to produce a xcex2-hydroxyester of general formula C 
in which R1, R2, R3, R4, R5, R18, R19 and R20 have the meaning indicated above, and R17 represents OR6 and R6 represents a lower alkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy lower alkyl or aryl or lower aryl alkyl;
said compound of general formula C is cyclized in order to produce the xcex2-hydroxylactonic compound of general formula D 
in which R1, R2, R3, R4, R5, R18, R19 and R20 have the meaning indicated above,
the lactone of general formula D is opened in order to produce the compound of formula E 
in which R1, R2, R3, R4, R5, R17, R18, R19 and R20 have the meaning indicated above; R16 represents OR21 in which R21 represents H or a lower alkyl; and R17 represents OR6 or NHR6 and R6 represents H, a lower alkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxy lower alkyl or aryl or lower aryl alkyl.
Certain compounds of general formula E can also be obtained by hydrolysis of the ester function of the corresponding compounds of general formula D. The compounds of general formula E in which R16 and/or R17 represent, independently, the hydroxy radical, can be esterified or amidified under standard conditions known to a person skilled in the art in order to obtain the corresponding esters or amides of general formula E.
In the above process, the R2, R3, R4 and R5 groups can be protected if necessary according to standard protection methods (Greene, T., Protective Groups in Organic Synthesis 10-86 (John Wiley and Sons 1981)). During this process, the reduction is carried out using a reducing agent in an appropriate solvent, such as, for example, sodium borohydride in methanol. The stage corresponding to the formation of compound of general formula B starting from compound of general formula A is implemented under oxidizing conditions, such as, for example, with lead tetraacetate, periodic acid or sodium metaperiodate in an appropriate solvent, such as, for example, acetic acid. The treatment with a functionalized alkylating agent can be implemented using a metallic derivative for example, of lithium or zinc, of a carboxylic ester in an anhydrous aprotic solvent such as, for example, tetrahydrofuran. The lactonization stage which allows compound of general formula D to be obtained starting from compound of general formula C is generally carried out under acid conditions, such as, for example, by treatment with trifluoroacetic acid or hydrochloric gas dissolved in an anhydrous solvent such as dichloromethane or dioxan. The opening of the lactonic ring of compound of general formula D in order to obtain compound of general formula E, can be carried out, for example, by hydrolysis under alkaline conditions followed by neutralization.
Examples of substituted camptothecins used as starting products can be found in the U.S. Pat. Nos. 4,473,692, 4,604,463, 4,894,956, 5,162,532, 5,395,939, 5,315,007, 5,264,579, 5,258,516, 5,254,690, 5,212,317 and 5,341,745, the PCT Patent Applications Nos. US91/08028, US94/06451, US90/05172, US92/04611, US93/10987, US91/09598, EP94/03058 and EP95/00393 and the European Patent Application Nos. 325 247, 495 432, 321 122 and 540 099.
Therefore, the invention also relates to a preparation process for the compounds of formulae (B1) and (B2), characterized in that
a compound of general formula M 
in which R1, R18 and R19 have the meaning indicated above and R20 represents a hydrogen or a halogen atom, is coupled with a 2-halo-3-quinoline-methanol of general formula N 
in which R2, R3, R4 and R5 have the meaning indicated above and X represents a halogen atom, in order to produce the compound of formula O 
in which R1, R2, R3, R4, R5, R18, R19, R20 and X have the meaning indicated above;
then the compound of general formula O is cyclized in order to obtain the compound of general formula D as defined above.
In the above process, the R1, R2, R3 and R4 groups can be protected if necessary according to standard protection methods (Greene. T., Protective Groups in Organic Synthesis 10-86 (John Wiley and Sons 1981)). The formation of compound O starting from the compounds of general formulae M and N is carried out with a treatment known to a person skilled in the art under the name Mitsunobu""s reaction (refer to Mitsunobu, O. et al. Synthesis, p. 1 (1981)). The hydroxyl function of compound N is displaced by a nucleophile such as compound M or a deprotonated derivative of the latter, by a treatment with a phosphine, for example triphenylphosphine, and an azodicarboxylate derivative, for example diethyl azodicarboxylate, in an aprotic solvent such as, for example, tetrahydrofuran or N,N-dimethylformamide. The cyclization of compound O is preferably carried out in the presence of a palladium catalyst (for example palladium diacetate) under basic conditions (provided for example by an alkaline acetate optionally combined with a phase transfer agent, such as, for example, tetrabutylammonium bromide), in an aprotic solvent such as acetonitrile or N,N-dimethylformamide, at a temperature comprised between 50xc2x0 C. and 120xc2x0 C. (R. Grigg et al., Tetrahedron 46, page 4003 (1990)).
The compounds of general formula M are new. They can be prepared according to a process characterized in that
the carbonyl of a pyridine of general formula 
n which R1 and R20 have the meaning indicated above and R22 represents a halogen atom or a lower alkoxy, is protected with an acetal function, in order to produce the compound of general formula F 
in which R1, R20 and R22 have the meaning indicated above and the Z and Zxe2x80x2 groups represent, independently, a lower alkyl or form together a saturated hydrocarbon chain with 2 to 4 carbons:
a hydroxymethyl function is introduced into the compound of general formula F in order to obtain a compound of general formula G 
in which R1, R20, R22, Z and Zxe2x80x2 have the meaning indicated above,
then the alcohol function of the compound of general formula G is protected in order to produce a compound of general formula H 
in which R1, R20, R22, Z and Zxe2x80x2 have the meaning indicated above and R23 represents a protective group of the alcohol function.
the acetal of the compound of general formula H is deprotected in order to produce the compound of general formula Ixe2x80x2
in which R1, R20, R22 and R23 have the meaning indicated above,
the compound of formula Ixe2x80x2 is treated with a functionalized alkylating agent in order to produce a xcex2-hydroxyester of general formula J 
in which R1, R20, R22 and R23 have the meaning indicated above, and R17, R18 and R19 are as defined in general formula II
the protective group R23 of the compound of general formula J is cleaved in order to produce a compound of general formula K, 
in which R1, R18, R19, R20 and R22 have the meaning indicated above, and R17 represents OR6 or NHR6 and R6 represents H, a lower alkyl, cycloalkyl, lower alkyl cycloalkyl, lower alkenyl, lower alkyl lower alkoxy or aryl or lower alkyl aryl,
the compound of general formula K is cyclized into the compound of general formula L 
in which R1, R18, R19, R20 and R22 have the meaning indicated above, and finally
the R22 radical of compound L is converted into carbonyl in order to obtain the compound of general formula M 
in which R1, R18, R19, R20, and R22 have the meaning indicated above.
The carbonyl function of a 4-acyl-2-pyridine (obtained for example according to Lammattina J. L. J. Heterocyclic Chem. 20, p. 553 (1983)) is preferably protected by an acetal function, preferably a cyclic acetal, according to the standard conditions known to a person skilled in the art (Greene. T., Protective Groups in Organic Synthesis 10-86 (John Wiley and Sons 1981)). The intermediate thus obtained is treated with a sodium or potassium alcoholate in an aprotic solvent (for example acetonitrile), or the alcohol from which the alcoholate is derived, at a temperature comprised between 0xc2x0 C. and 100xc2x0 C. in order to produce the compound of general formula F. The latter can be lithiated in position 3 by treatment with an aryl- or alkyl-lithium (for example mesityl-lithium) in an ethereal solvent such as tetrahydrofuran at a temperature comprised between xe2x88x92100xc2x0 C. and 0xc2x0 C. A formylating electrophile such as N,N-dimethylformamide is added to the lithiated intermediate thus obtained, and the aldehyde thus obtained is treated, after hydrolysis, with a reducing agent such as sodium borohydride in order to produce the compound of general formula G. The protection of the alcohol function of compound of general formula G is carried out according to the standard conditions known to a person skilled in the art, in order to obtain a compound of general formula H. Examples of protective groups of the alcohol function include those which form ethers (i.e. methyl, methoxymethyl, tetrahydropyranyl, 2-methoxyethoxy methyl, benzyloxymethyl, t-butyl and benzyl (substituted or non substituted)), and esters (i.e. formate, acetate and isobutyrate). For other examples of protective groups of primary hydroxyls refer to Greene. T., Protective Groups in Organic Synthesis 10-86 (John Wiley and Sons 1981). The deprotection of the compound of general formula H in order to produce the compound of general formula Ixe2x80x2 is carried out under selective conditions maintaining the integrity of the R23 radical, for example, by treatment under acid conditions (for example by trifluoroacetic acid). The selective conditions for the protection and deprotection of functional groups are known to a person skilled in the art (Greene. T., Protective Groups in Organic Synthesis 10-86 (John Wiley and Sons 1981)). The treatment of compound of general formula Ixe2x80x2 with a functionalized alkylating agent in order to produce a xcex2-hydroxy ester of general formula J can be carried out using a lithium enolate or a zinc derivative of a carboxylic ester in an anhydrous aprotic solvent, for example, tetrahydrofuran. The protective group R23 of the compound of general formula J is cleaved in order to produce a compound of general formula K under deprotection conditions known to a person skilled in the art. For example, when R23 is a benzyl group, an alcoholic solution of the compound of general formula J with a palladium catalyst added to it can be subjected to a hydrogen atmosphere under a pressure of 0.5 to 10 Bar. The cyclization of the compound of general formula K thus obtained can be carried out under acid conditions (for example by treatment with trifluoroacetic acid, or hydrochloric gas dissolved in an anhydrous solvent such as dichloromethane or dioxan) in order to produce a xcex2-hydroxylactonic ring with seven members such as in the compound of general formula L. The compounds of general formula L can be converted into pyridones of general formula M, for example, by treatment with warm hydrochloric acid, or by treatment with trimethylsilyl iodide.
The 2-halo-3-quinoline methanols of general formula N can be obtained starting from the acetanilides of general formula P 
in which R2, R3 and R4 have the meaning indicated in the general formulae of compounds I and II. In the processes below, the R2, R3 and R4 groups can be protected if necessary according to standard protection methods (Greene. T., Protective Groups in Organic Synthesis 10-86 (John Wiley and Sons 1981)).
The compounds of formula N can therefore be obtained according to the following process: the said anilines of formula P are N-acetylated by treatment with an acetylating agent such as, for example, acetic anhydride. The acetanilides thus obtained are treated at a temperature comprised between 50xc2x0 C. and 100xc2x0 C., preferably approximately 75xc2x0 C., with a reagent known to a person skilled in the art under the name Vilsmeyer""s reagent (obtained by the action of phosphoryl oxychloride on NN-dimethylformamide at a temperature comprised between 0xc2x0 C. and 10xc2x0 C.) in order to produce the corresponding 2-chloro-3-quinolinecarbaldehyde (for example, refer to Meth-Cohn et al. J. Chem. Soc., Perkin Trans. I p. 1520 (1981); Meth-Cohn et al. J. Chem. Soc., Perkin Trans. I p. 2509 (1981); and Nakasimhan et al. J. Am. Chem. Soc., 112 p. 4431 (1990)). The chlorine in position 2 of the 2-chloro-3-quinolinecarbaldehydes can be substituted by iodine or bromine by heating the product in an inert solvent such as acetonitrile in the presence of an iodine or bromine salt (for example sodium iodide or tetrabutylammonium bromide). A trace of acid such as concentrated hydrochloric acid may be necessary to catalyze this conversion. The 2-halo-3-quinolinecarbaldehydes are easily reduced to the corresponding 2-halo-3-quinolinemethanols of general formula N, under standard conditions known to a person skilled in the art such as treatment in an alcoholic solvent (for example methanol) with sodium borohydride at a temperature comprised between 0xc2x0 C. and 40xc2x0 C.
The compounds of formula N can also be obtained according to the following process: the anilines of general formula P as defined above are acylated by reaction with a nitrile (such as chloroacetonitrile or propionitrile) in the presence of boron trichloride and another Lewis acid such as aluminium trichloride, titanium tetrachloride or diethylaluminium chloride in an aprotic solvent or a mixture of aprotic solvents, followed by hydrolysis (cf. Sugasawa T. et al. J. Am. Chem. Soc. 100 p. 4842 (1978)). The intermediate thus obtained is then treated with ethylmalonyl chloride in an aprotic solvent such as acetonitrile in the presence of a base such as triethylamine, then treated with an alkaline alcohol, for example, sodium methylate in methanol, in order to produce an ethyl 2-hydroxy-3-quinolinecarboxylate substituted in position 4. This is converted into ethyl 2-chloro-3-quinolinecarboxylate by treatment with phosphoryl oxychloride. When position 4 of the quinoline carries a chloromethyl group, a nucleophile substitution can be carried out by treatment with a secondary amine such as, for example, dimethylamine, N-methylpiperazine, morpholine or piperidine. The ethyl 2-chloro-3-quinolinecarboxylate is then reduced with diisobutylaluminium hydride in an aprotic solvent such as dichloromethane in order to produce the 2-chloro-3-quinolinemethanol of general formula N. Analogues of intermediate compounds of general formula N have been described in the literature and in particular in the PCT Application 95/05427.
The invention also offers, as a new industrial product, a compound of general formula MX represented below: 
wherein R is a lower alkyl group, and preferably ethyl.
This product can be used for the manufacture of medicaments.
The compound of formula MX is synthesized according to a new process which is part en e of the invention and includes the following successive stages:
the racemic t-butyl ester represented below 
(for its preparation, refer in particular to the Patent Application WO 97/00876) is treated with trifluoroacetic acid for 18 hours at ambient temperate in order to produce the corresponding carboxylic acid;
then the quinidine salt of the acid obtained previously is heated in isopropyl alcohol at a temperature greater than 30xc2x0 C., and preferably at about 50xc2x0 C., before leaving the reaction medium to cool down to ambient temperature, so that the salt of one of the enantiomers of the above-mentioned acid crystallized while the salt of the other enantiomer, the anion of which is represented below, remains in solution 
the solution in isopropyl alcohol of the salt of the enantiomer which has not crystallized is concentrated and treated with hydrochloric acid and agitated, producing the compound of general formula AX represented below 
the compound of general formula AX is then put in contact with palladium on damp carbon, then ammonium formate is added to the mixture in order to produce the debenzylated product of general formula BX represented below 
then the compound of general formula BX is cyclized by the action of dicyclohexylcarbodiimide in order to obtain the lactonic compound of general formula CX represented below 
finally, the xe2x80x94OCH3 group of the lactonic compound of general formula CX is converted into carbonyl, by the action of sodium iodide and trimethylsilyl chloride, in order to obtain a compound of general formula MX represented below. 
For the process described above, the reaction leading from the compound of general formula AX to the compound of general formula BX will preferably take place in methanol, and preferably by heating the reaction medium to about 40xc2x0 C. after the addition of the amimonium formate. The cyclization of the compound of general formula BX in order to produce the compound CX can be carried out in THF, preferably at a temperature of about 50xc2x0 C., while the reaction will preferably be carried out at ambient temperature with acetonitrile as solvent in the reaction leading from the compound of general formula CX to the compound of general formula MX.
In the particular case where R represents an ethyl group, the compound of formula MX is synthesized according to the process constituted by the following successive stages:
the racemic t-butyl ester represented below 
(for its preparation, refer in particular to the Patent Application WO 97/00876) is treated with trifluoroacetic acid for 18 hours at ambient temperature in order to produce the corresponding carboxylic acid;
the quinidine salt of 3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoic acid is heated in isopropyl alcohol at a temperature higher than 30xc2x0 C., and preferably at about 50xc2x0 C., before leaving the reaction medium to cool down to ambient temperature, so that the salt of the (+) enantiomer of 3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoic acid crystallizes whilst the salt of the (xe2x88x92) isomer the anion of which is represented below, remains in solution 
the solution in isopropyl alcohol of the salt of the (xe2x88x92) enantiomer of 3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoic acid is concentrated and treated with hydrochloric acid and agitated, producing the compound of formula AXxe2x80x2 represented below 
the compound AXxe2x80x2 is then put in contact with palladium on damp carbon, the ammonium formate is added to the mixture in order to produce the debenzylated product BXxe2x80x2 represented below 
then the compound of formula BXxe2x80x2 is cyclized by the action of dicyclohexylcarbodiimnide in order to obtain the lactonic compound of formula CXxe2x80x2 represented below 
finally, the xe2x80x94OCH3 group of the lactonic compound of formula CXxe2x80x2 is converted into carbonyl, by the action of sodium iodide and trimethylsilyl chloride, in order to obtain (+)-5-ethyl-5-hydroxy-1,3,4,5,8,9hexahydrooxepino [3,4-c]pyridin-3,9-dione (or (+)-EHHOPD) represented below. 
A subject of the invention is also, as new industrial products and in particular as new industrial products intended for the preparation of the products of general formula (B1) and (B2); the products of general formulae Ixe2x80x2, M and MX as described above.
Certain compounds of the invention can be prepared in the form of pharmaceutically acceptable salts according to the usual methods. Acceptable salts include, by way of example and in a non-limitative fashion, the addition salts with inorganic acids such as hydrochloride, sulphate, phosphate, diphosphate, hydrobromide, and nitrate or with organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methane sulphonate, p-toluenesulphonate, pamoate, salicylate, oxalate and stearate. The salts formed from bases such as sodium or potassium hydroxide also form part of the field of application of the present invention, when they are useable. For other examples of pharmaceutically acceptable salts one can refer to xe2x80x9cPharmaceutical Saltsxe2x80x9d, J. Pharm. Sci. 66:1 (1977).
The compounds of the present invention possess useful pharmacological properties. Thus the compounds of the present invention have an inhibitory effect on topoisomerase I and/or II and am anti-tumoral activity. The state of the art suggests that the compounds according to the invention have an anti-parasitic and/or anti-viral activity. The compounds according to the present invention can also be used in different therapeutic applications.
An illustration of the pharmacological properties of the compounds according to the invention will be found hereafter in the experimental part.
The compounds can inhibit topoisomerase, for example of type I and/or II, in a patient, for example a mammal such as man, by administration to this patient of a therapeutically effective quantity of a compound of formula (B1) or a compound of formula (B2).
The compounds according to the invention also have an anti-tumoral activity. They can be used for the treatment of tumors, for example tumors expressing a topoisomerase, in a patient by administration to the latter of a therapeutically effective quantity of a compound of formula (B1) or a compound of formula (B2). Examples of tumors or cancers include cancers of the oesophagus, the stomach, the intestines, the rectum, the oral cavity, the pharynx, the larynx, the lung, the colon, the breast, the cervix uteri, the corpus endometrium, the ovaries, the prostate, the testicles, the bladder, the kidneys, the liver, the pancreas, the bone, the connective tissues, the skin, the eyes, the brain and the central nervous system, as well as cancer of the thyroid, leukemia, Hodgkin""s disease, lymphomas other than those related to Hodgkin, multiple myelomas and others.
They can also be used for the treatment of parasitic infections by inhibition of the hemoflagellates (for example in trypanosomia or leishmania infections) or by inhibition of the plasmodia (such as for example in malaria), but also the treatment of viral infections and diseases.
These properties make the products of formula (B1) and (B2) suitable for pharmaceutical use. A subject of the present Application is also, as medicaments, the products of formula (B1) and (B2) as defined above as well as the addition salts with pharmaceutically acceptable mineral or organic acids of said products of formula (B1) and (B2), as well as the pharmaceutical compositions containing at least one of the medicaments as defined above as active ingredient.
An object of the invention is therefore methods of treatment of diseases related with topoisomerase I and/or topoisomerase II disorders, and especially cancer, viral and parasitic diseases, comprising the administration of a therapeutically efficient dose of a camptothecin analog, said camptothecin analog being characterized in that it features a xcex2-hydroxy lactone instead of the xcex1-hydroxy lactone of natural camptothecin.
Another object of the invention is methods of treatment of diseases related with topoisomerase I and/or topoisomerase II disorders, and especially cancer, viral and parasitic diseases, comprising the administration of a therapeutically efficient dose of a compound of general formula (B1) or a compound of general formula (B2).
In particular, an object of the invention is methods of treatment as previously described comprising the administration of any of the xcex2-hydroxy lactone camptothecin analogues disclosed in the present application, especially those of general formula (HCPT) and those described in the examples.
The invention also relates to pharmaceutical compositions containing a compound according to the invention or an addition salt with a pharmaceutically acceptable acid of it, in combination with a pharmaceutically acceptable support according to the chosen administration method (for example oral, intravenous, intraperitoneal, intramuscular, trans-dermic or sub-cutaneous). The pharmaceutical composition (for example therapeutic) can be in the form of a solid, liquid, liposome or lipidic micella.
The pharmaceutical composition can be in solid form, for example, powders, pills, granules, tablets, liposomes, gelatin capsules or suppositories. The pill, tablet or gelatin capsule can be covered in a substance which is capable of protecting the composition from the action of gastric acid or enzymes in the stomach of the subject for a sufficient period of time to allow this composition to pass in a non-digested form into the small intestine of the latter. The compound can also be administered locally, for example, at the same location as the tumor. The compound can also be administered according to a sustained release process (for example a sustained release composition or an infusion pump). The appropriate solid supports can be, for example, calcium phosphate, magnesium stearate, magnesium carbonate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax. The pharmaceutical compositions containing a compound according to the invention can also be presented in liquid form such as, for example, solutions, emulsions, suspensions or a sustained release formulation. The appropriate liquid supports can be, for example, water, organic solvents such as glycerol or glycols such as polyethylene glycol, similarly their mixtures, in varied proportions, in water.
A subject of the invention is also the use of the products of formula (B1) or (B2) as defined above for the preparation of medicaments intended to inhibit topoisomerase and more particularly topoisomerase of type I or type II, medicaments intended for the treatment of tumors, medicaments intended for the treatment of parasitic infections, as well as medicaments intended for the treatment of viral diseases.
Of course, the products of general formula (HCPT), (I), (II), (I)OP and (II)OP can be used according to the invention analogously to the products of formula (B1) or (B2).
The dose of a compound according to the present invention envisaged for the treatment of the diseases or disorders mentioned above, varies according to the administration method, the age and body weight of the subject as well as the state of the latter and it will be decided definitively by the attending doctor or vet. Such a quantity determined by the attending doctor or vet is called here xe2x80x9ceffective therapeutic quantityxe2x80x9d.
Unless defined in another manner, all the technical and scientific terms used here have the same meaning as that commonly understood by an ordinary specialist in the field to which the invention belongs. Similarly, all publications, Patent Applications, all Patents and all other references mentioned here are incorporated by way of reference.
The following examples are presented to illustrate the above procedures and must in no case be considered as a limit to the scope of the invention.